The present invention is directed to novel urea, thiourea, thiocarbamyl and carbamyl 4-azasteroidal 5-alpha-reductase inhibitors.
The art reveals that certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, male pattern baldness and benign prostatic hypertrophy, art the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone or similar androgenic hormones in the metabolic system. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethyl-isobutyranilide. See Neri, et al., Endo., Vol. 91, No. 2 (1972). However, these products, though devoid of hormonal effects, are peripherally active, competing with the natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host
It is now known in the art that the principal mediator of androgenic activity in some target organs is 5.alpha.-dihydrotestosterone, and that it is formed locally in the target organ by the action of testosterone-5.alpha.-reductase. It is also known that inhibitors of testosterone-5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation. A number of 4-aza steroid compounds are known in the art that are 5.alpha.-reductase inhibitors. For example, see U.S. Pat. Nos. 2,227,876, 3,239,417, 3,264,301 and 3,285,918; French Patent No. 1,465,544; Doorenbos and Solomons, J. Pharm. Sci. 62, 4, pp. 638-640 (1973); Doorenbos and Brown, J..Pharm. Sci., 60, 8, pp. 1234-1235 (1971); and Doorenbos and Kim, J. Pharm. Sci. 63, 4, pp. 620-622 (1974).
In addition. U.S. Pat. Nos. 4,377,584, 4,220,775, 4,859,681, 4,760,071 and the articles J. Med. Chem. 27, p. 1690-1701 (1984) and J. Med. Chem. 29, 2998-2315 (1986) of Rasmusson, et al., U.S. Pat. No. 4,845,104 to Carlin, et al., and U.S. Pat. No. 4,732,897 to Cainelli, et al. describe 4-aza-17.beta.-substituted-5.alpha.-androstan-3-ones which are said to be useful in the treatment of DHT-related hyperandrogenic conditions.
However, despite the suggestion in the prior art that hyperandrogenic diseases are the result of a single 5.alpha.-reductase, there are reports regarding the presence of other 5.alpha.-reductase isozymes in both rats and humans. For example, in human prostate, Bruchovsky, et al. (See J. Clm. Endocrinol. Metab. 67, 806-816, 1988) and Hudson (see J. Steroid Biochem. 26, p 349-353, 1987) found different 5.alpha.-reductase activities in the stromal and epithelial fractions. Additionally, Moore and Wilson described two distinct human reductases with peaks of activities at either pH 5.5 or pH 7-9. (See J. Biol. Chem. 251, 19, p. 5895-5900, 1976.)
Recently, Andersson and Russell isolated a cDNA which encodes a rat liver 5.alpha.-reductase (see J. Biol. Chem. 264 pp. 16249-55 (1989). They found a single mRNA which encodes both the liver and prostatic reductases of rats. A sequence of this rat gene was later used to select a human prostatic cDNA encoding a 5.alpha.-reductase termed "5.alpha.-reductase 1". (See Proc. Nat'l. Acad. Sci. 87, p. 3640-3644, 1990.)
More recently, a second, more abundant reductase (5.alpha.-treductase 2) has been cloned from human prostate with properties identified with the form found in crude human prostatic extracts. (See Nature, 354, p. 159-161, 1991.)
Further, "Syndromes of Androgen Resistance"--The Biology of Reproduction, Vol. 46, p. 168-173 (1992) by Jean O. Wilson indicates that the 5.alpha.-reductase 1 enzyme is associated with hair follicles.
Thus, the art supports the existence of at least two genes for 5.alpha.-reductase and two distinct isozymes of 5.alpha.-reductase in humans. Both forms are present in prostatic tissue in which, 5.alpha.-reductase 2, is the more abundant, and the other isozyme, 5.alpha.-reductase 1, is believed to be more abundant in scalp tissue.
In the treatment of hyperandrogenic disease conditions. e.g. benign prostatic hyperplasia (BPH) it would be desirable to have one drug entity which is active against both enzymes 1 and 2 in the prostate to substantially inhibit dihydrotesterone (DHT) production. Alternatively, it would be desirable to have a drug entity which is highly selective for inhibiting the scalp associated enzyme 5.alpha.-reductase 1, for use in treating diseases of the skin and scalp, e.g. acne and alopecia. This latter drug could be used in combination with PROSCAR.RTM. (finasteride) which is highly selective for the prostatic enzyme 5.alpha.-reductase 2 for combination therapy in the treatment of BPH.